Signaling between neighboring cells is crucial for many cell fate decisions during development. Surprisingly, the same secreted signals are often used in different tissues to elicit apparently unrelated cellular responses. Our goal is to understand better the molecular mechanisms underlying this phenomenon, using a relatively simple example of tissue-specific regulation by the Drosophila secreted protein Wingless (Wg). In the developing fly wing, Wg is required for the formation of sensory bristles. However, in the eye Wg signaling prevents cells from adopting a bristle cell fate. The bristle precursor cells in both tissues receive the Wg signal, but they interpret the signal differently. To learn more about the tissue-specific aspects of Wg signaling, two approachers are proposed. We have identified the daughterless (da) gene as potential direct target of Wg-dependent bristle inhibition in the eye. We will determine the molecular mechanism of this regulation and whether Da is a target of Wg signaling in the wing. The second approach is to characterize two genes whose mutant phenotypes indicate that they play important roles in tissue-specific Wg signaling. One gene encodes a protein kinase that is required for Wg regulation of bristle formation in the eye but not in the wing. Genetic epitasis analysis as well as biochemical characterization of the kinase will determine its relationship to known components of the Wg signaling pathway. The second gene acts as a positive effector of Wg signaling in the eye, but it antagonizes the pathway in the wing. This gene will be cloned and sequenced to elucidate the role it plays in Wg signaling. We expect that the two approaches will converge on a model to explain the tissue- specific control of bristle formation by Wg. Wg is one of the best characterized members of a large family of secreted proteins (known as Wnts) conserved throughout the animal kingdom. Wnts have been found to play many important roles in the development of both invertebrates and vertebrates. In addition, Wnt signaling has been implicated in tumorigenesis in mice and humans. Since the machinery for Wnt signal transduction is also evolutionarily conserved, understanding tissue specific mechanisms of Wg signaling in flies should have broad relevance to other organisms.